Claims (15)
1. Spoj koji je benzimidazol formule (I):
[image]
u kojem:
R1 je -(CH2)m-R7,
[image]
R2 je H, halo, -(CH2)m-NH2, -(CH2)n-C(=NH)-NH2 ili -(CH2)n-NH-(CH2)m-NHR9;
R3je H, F ili Cl;
svaki od R4, R5 i R6 je nezavisno H ili F;
R7 je C1-C6 alkil, CF3, -SO2R11, -NH-(CH2)2-(NH)r-R8, -NH-CH(R8R9) ili grupa sljedeće formule (A):
[image]
W je -(CH2)m-, -CH2-O-CH2-, -CH2-S-CH2-, -(CH2)r-S(O)2-CH2- ili -(CH2)r-NR8-CH2-;
m je cijeli broj od 1 do 3;
n je 1 ili 2;
p je 1 i V je CH; ili p je 0 i V je N;
q je 0 ili 1;
r je 0 ili 1;
R8 je H, -SO2R11, -SO2CF3, -COR11, -C(O)OR11, -CON(R9)2 ili -(CH2)nSO2R11;
R9 je H ili C1-C6 alkil, svaki R9 je isti ili različit kada su prisutna dva;
R10 je -SO2R11, -SO2CF3, -COR11, -CON(R9)2 ili -(CH2)nSO2R11; i
R11 je C1-C6 alkil;
ili njegova farmaceutski prihvatljiva sol.1. A compound which is a benzimidazole of the formula (I):
[image]
in which:
R1 is -(CH2)m-R7,
[image]
R2 is H, halo, -(CH2)m-NH2, -(CH2)n-C(=NH)-NH2 or -(CH2)n-NH-(CH2)m-NHR9;
R 3 is H, F or Cl;
each of R 4 , R 5 and R 6 is independently H or F;
R7 is C1-C6 alkyl, CF3, -SO2R11, -NH-(CH2)2-(NH)r-R8, -NH-CH(R8R9) or a group of the following formula (A):
[image]
W is -(CH2)m-, -CH2-O-CH2-, -CH2-S-CH2-, -(CH2)r-S(O)2-CH2- or -(CH2)r-NR8-CH2-;
m is an integer from 1 to 3;
n is 1 or 2;
p is 1 and V is CH; or p is 0 and V is N;
q is 0 or 1;
r is 0 or 1;
R8 is H, -SO2R11, -SO2CF3, -COR11, -C(O)OR11, -CON(R9)2 or -(CH2)nSO2R11;
R 9 is H or C 1 -C 6 alkyl, each R 9 being the same or different when two are present;
R10 is -SO2R11, -SO2CF3, -COR11, -CON(R9)2 or -(CH2)nSO2R11; and
R 11 is C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt thereof.
2. Spoj prema zahtjevu 1 gdje R1 je -(CH2)m-R7 u kojoj m je 2 ili 3 i R7 je izabran između:
(i) -NH-(CH2)2-(NH)r-R8 gdje r je 0 ili 1 i R8 je izabran između -SO2Me, -SO2Et i -SO2CF3;
(ii) C1-C6 alkil, CF3 ili -SO2R11;
(iii) -NH-CH(R8R9) gdje R8 je -CONH2 ili -CONMe2 i R9 je C1-C6 alkil.
(iv) grupa formule (A) u kojoj p je 1, q je 0, V je CH i W je -(CH2)r-S(O)2-CH2- ili -(CH2)r-NR8-CH2- u kojoj r je 0 i R8 je -SO2Me ili -SO2Et;
(v) grupa formule (A) u kojoj p je 0, V je N, W je -(CH2)m-u kojoj m je cijeli broj od 1 do 3, q je 1 i R10 je -SO2Me, -SO2Et, -CONH2 ili -CONMe2; i
(vi) grupa formule (A) u kojoj p je 0, V je N, q je 0 i W je -CH2-O-CH2-, -CH2-S-CH2-, -(CH2)r-S(O)2-CH2-ili -(CH2)r-NR8-CH2-u kojoj r je 0 ili 1 i R8 je -SO2Me, -SO2Et ili -COMe.2. A compound according to claim 1 where R1 is -(CH2)m-R7 in which m is 2 or 3 and R7 is selected from:
(i) -NH-(CH2)2-(NH)r-R8 where r is 0 or 1 and R8 is selected from -SO2Me, -SO2Et and -SO2CF3;
(ii) C1-C6 alkyl, CF3 or -SO2R11;
(iii) -NH-CH(R8R9) where R8 is -CONH2 or -CONMe2 and R9 is C1-C6 alkyl.
(iv) a group of formula (A) in which p is 1, q is 0, V is CH and W is -(CH2)r-S(O)2-CH2- or -(CH2)r-NR8-CH2- in which r is 0 and R8 is -SO2Me or -SO2Et;
(v) a group of formula (A) wherein p is 0, V is N, W is -(CH2)m-wherein m is an integer from 1 to 3, q is 1 and R10 is -SO2Me, -SO2Et, -CONH2 or -CONMe2; and
(vi) a group of formula (A) wherein p is 0, V is N, q is 0 and W is -CH2-O-CH2-, -CH2-S-CH2-, -(CH2)r-S(O)2- CH2-or -(CH2)r-NR8-CH2-in which r is 0 or 1 and R8 is -SO2Me, -SO2Et or -COMe.
3. Spoj prema zahtjevu 1 u kojem:
R1 je
[image]
u kojem R8 je H, -SO2R11, -COMe, -C(O)OR11, -CON(R9)2 ili -(CH2)nSO2R11.3. Compound according to claim 1 in which:
R1 is
[image]
wherein R8 is H, -SO2R11, -COMe, -C(O)OR11, -CON(R9)2 or -(CH2)nSO2R11.
4. Spoj prema zahtjevu 3 gdje
-SO2R11 je -SO2Me ili -SO2Et;
-CON(R9)2 je -CONH2 ili -CONMe2; i
-(CH2)nSO2R11 je -CH2CH2SO2Me.4. Compound according to claim 3 where
-SO2R11 is -SO2Me or -SO2Et;
-CON(R9)2 is -CONH2 or -CONMe2; and
-(CH2)nSO2R11 is -CH2CH2SO2Me.
5. Spoj prema bilo kojem od zahtjeva 1 do 3 u kojem R2 je Cl ili -CH2NH2.5. A compound according to any one of claims 1 to 3 in which R 2 is Cl or -CH 2 NH 2 .
6. Spoj prema zahtjevu 1 ili 2 gdje je grupa formule (A) izabrana između sljedećih struktura:
[image] 6. Compound according to claim 1 or 2, where the group of formula (A) is selected from the following structures:
[image]
7. Spoj prema zahtjevu 1, koji je izabran između:
1-{[5-Kloro-1-(4,4,4-trifluorobutil)-1H-1,3-benzodiazol-2-il]metil}-3,3-difluoro-2,3-dihidro-1H-indol-2-ona;
1-({5-Kloro-1-[3-(-(4-metansulfonilpiperazin-1-il)propil]-1H-1,3-benzodiazol-2-il}metil)-3,3-difluoro-2,3-dihidro-1H-indol-2-ona;
1-[(5-Kloro-1-{3-[(2-metansulfoniletil)amino]propil}-1H-1,3-benzodiazol-2-il)metil]-3,3-difluoro-2,3-dihidro-1H-indol-2-ona;
1-({5-Kloro-1-[3-(3-metansulfonilpirolidin-1-il)propil]-1H-1,3-benzodiazol-2-il}metil)-3,3-difluoro-2,3-dihidro-1H-indol-2-ona;
1-{[5-Kloro-1-(3-metansulfonilpropil)-1H-1,3-benzodiazol-2-il]metil}-3,3-difluoro-2,3-dihidro-1H-indol-2-ona;
terc-Butil 4-{5-Kloro-2-[(3,3-difluoro-2-okso-2,3-dihidro-1H-indol-1-il)metil]-1H-1,3-benzodiazol-1-il}piperidin-1-karboksilata;
1-{[5-Kloro-1-(piperidin-4-il)-1H-1,3-benzodiazol-2-il]metil}-3,3-difluoro-2,3-dihidro-1H-indol-2-ona;
1-{[5-Kloro-1-(1-metansulfonilpiperidin-4-il)-1H-1,3-benzodiazol-2-il]metil}-3,3-difluoro-2,3-dihidro-1H-indol-2-on;
1-({5-Kloro-1-[1-(etansulfonil)piperidin-4-il]-1H-1,3-benzodiazol-2-il}metil)-3,3-difluoro-2,3-dihidro-1H-indol-2-ona;
1-{[5-Kloro-1-(oksan-4-il)-1H-1,3-benzodiazol-2-il]metil}-3,3-difluoro-2,3-dihidro-1H-indol-2-ona;
1-{[5-Kloro-1-(oksan-4-il)-1H-1,3-benzodiazol-2-yl]metil}-3,3,6-trifluoro-2,3-dihidro-1H-indol-2-ona;
1-{[5-Kloro-1-(oksan-4-il)-1H-1,3-benzodiazol-2-il]metil}-3,3,7-trifluoro-2,3-dihidro-1H-indol-2-on;
1-{[5-(Aminometil)-1-(3-metilbutil)-1H-1,3-benzodiazol-2-il]metil}-3,3-difluoro-2,3-dihidro-1H-indol-2-ona;
1-{[5-(Aminometil)-1-(3-metilbutil)-1H-1,3-benzodiazol-2-il]metil}-3,3,4-trifluoro-2,3-dihidro-1H-indol-2-ona;
1-{[5-(Aminometil)-1-(3-metilbutil)-1H-1,3-benzodiazol-2-yl]metil} -4-kloro-3,3-difluoro-2,3-dihidro-1H-indol-2-ona; i
1-{[5-(Aminometil)-1-(3-metilbutil)-1H-1,3-benzodiazol-2-yl]metil}-3,3,5-trifluoro-2,3-dihidro-1H-indol-2-ona;
i njihovih farmaceutski prihvatljivih soli.7. The compound according to claim 1, which is chosen between:
1-{[5-Chloro-1-(4,4,4-trifluorobutyl)-1H-1,3-benzodiazol-2-yl]methyl}-3,3-difluoro-2,3-dihydro-1H-indole -2-she;
1-({5-Chloro-1-[3-(-(4-methanesulfonylpiperazin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-3,3-difluoro-2, 3-dihydro-1H-indol-2-one;
1-[(5-Chloro-1-{3-[(2-methanesulfonylethyl)amino]propyl}-1H-1,3-benzodiazol-2-yl)methyl]-3,3-difluoro-2,3-dihydro -1H-indol-2-one;
1-({5-Chloro-1-[3-(3-methanesulfonylpyrrolidin-1-yl)propyl]-1H-1,3-benzodiazol-2-yl}methyl)-3,3-difluoro-2,3- dihydro-1H-indol-2-one;
1-{[5-Chloro-1-(3-methanesulfonylpropyl)-1H-1,3-benzodiazol-2-yl]methyl}-3,3-difluoro-2,3-dihydro-1H-indol-2-one ;
tert-Butyl 4-{5-Chloro-2-[(3,3-difluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-1,3-benzodiazol-1 -yl}piperidine-1-carboxylate;
1-{[5-Chloro-1-(piperidin-4-yl)-1H-1,3-benzodiazol-2-yl]methyl}-3,3-difluoro-2,3-dihydro-1H-indole-2 -she;
1-{[5-Chloro-1-(1-methanesulfonylpiperidin-4-yl)-1H-1,3-benzodiazol-2-yl]methyl}-3,3-difluoro-2,3-dihydro-1H-indole -2-one;
1-({5-Chloro-1-[1-(ethanesulfonyl)piperidin-4-yl]-1H-1,3-benzodiazol-2-yl}methyl)-3,3-difluoro-2,3-dihydro- 1H-indol-2-one;
1-{[5-Chloro-1-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]methyl}-3,3-difluoro-2,3-dihydro-1H-indole-2 -she;
1-{[5-Chloro-1-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]methyl}-3,3,6-trifluoro-2,3-dihydro-1H-indole -2-she;
1-{[5-Chloro-1-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]methyl}-3,3,7-trifluoro-2,3-dihydro-1H-indole -2-one;
1-{[5-(Aminomethyl)-1-(3-methylbutyl)-1H-1,3-benzodiazol-2-yl]methyl}-3,3-difluoro-2,3-dihydro-1H-indole-2 -she;
1-{[5-(Aminomethyl)-1-(3-methylbutyl)-1H-1,3-benzodiazol-2-yl]methyl}-3,3,4-trifluoro-2,3-dihydro-1H-indole -2-she;
1-{[5-(Aminomethyl)-1-(3-methylbutyl)-1H-1,3-benzodiazol-2-yl]methyl}-4-chloro-3,3-difluoro-2,3-dihydro-1H -indol-2-one; and
1-{[5-(Aminomethyl)-1-(3-methylbutyl)-1H-1,3-benzodiazol-2-yl]methyl}-3,3,5-trifluoro-2,3-dihydro-1H-indole -2-she;
and their pharmaceutically acceptable salts.
8. Farmaceutski sastav koji sadrži spoj kao što je definirano prema bilo kojem od zahtjeva 1 do 7 i farmaceutski prihvatljiv nosač ili razblaživač.8. A pharmaceutical composition comprising a compound as defined according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier or diluent.
9. Spoj kao što je definiran prema bilo kojem od zahtjeva 1-7, za upotrebu u liječenju ljudskog ili životinjskog tijela terapijom.9. A compound as defined according to any one of claims 1-7, for use in treating the human or animal body with therapy.
10. Spoj kako je definirano prema bilo kojem od zahtjeva 1 do 7 za upotrebu u liječenju ili prevenciji RSV infekcije.10. A compound as defined according to any one of claims 1 to 7 for use in the treatment or prevention of RSV infection.
11. Proizvod koji sadrži:
(a) spoj koji je definiran prema bilo kojem od zahtjeva 1 do 7; i
(b) jedno ili više drugih terapeutskih sredstava;
za simultanu, odvojenu ili sekvencionalnu upotrebu u liječenju subjekta koji pati od ili je podložan RSV infekciji.11. Product containing:
(a) a compound as defined according to any one of claims 1 to 7; and
(b) one or more other therapeutic agents;
for simultaneous, separate, or sequential use in the treatment of a subject suffering from or susceptible to RSV infection.
12. Proizvod prema zahtjevu 11, gdje je drugo terapeutsko sredstvo:
(i) RSV inhibitor (N)-proteina nukleokapsida;
(ii) inhibitor proteina, kao što je onaj koji inhibira fosfoproteinski (P) protein i/ili veliki (L) protein;
(iii) anti-RSV monoklonalna antitijela, kao što je antitijelo F-proteina;
(iv) imunomodulatorni spoj receptora sličnog tolu;
(v) anti-virusni lijekovi respiratornog virusa, kao što su spojevi protiv grupa i/ili protiv rinovirusa; i/ili
(vi) anti-inflamatorni spoj.12. The product according to claim 11, where the second therapeutic agent is:
(i) RSV inhibitor of (N)-nucleocapsid protein;
(ii) a protein inhibitor, such as one that inhibits a phosphoprotein (P) protein and/or a large (L) protein;
(iii) anti-RSV monoclonal antibodies, such as F-protein antibody;
(iv) an immunomodulatory toll-like receptor compound;
(v) respiratory virus antivirals, such as anti-group and/or anti-rhinovirus compounds; and/or
(vi) anti-inflammatory compound.
13. Farmaceutski sastav koji sadrži (a) spoj kao što je definirano u bilo kojem od zahtjeva 1 do 7, i (b) jedno ili više terapeutskih sredstava kao što je definirano prema zahtjevu 12, zajedno s farmaceutski prihvatljivim nosačem ili razblaživačem.13. A pharmaceutical composition comprising (a) a compound as defined in any of claims 1 to 7, and (b) one or more therapeutic agents as defined in claim 12, together with a pharmaceutically acceptable carrier or diluent.
14. Postupak za dobivanje farmaceutski prihvatljive soli kao što je definirano prema zahtjevu 1, gdje postupak obuhvaća tretiranje benzimidazola formule (I) kako je definirano u zahtjevu 1 s pogodnom kiselinom u pogodnom rastvaraču.14. A process for obtaining a pharmaceutically acceptable salt as defined according to claim 1, where the process comprises treating a benzimidazole of formula (I) as defined in claim 1 with a suitable acid in a suitable solvent.
15. Postupak prema zahtjevu 14, gdje je kiselina izabrana između klorovodonične kiseline, bromovodonične kiseline, jodovodonične kiseline, sumporne kiseline, dušikove kiseline, fosforne kiseline, metansulfonske kiseline, benzensulfonske kiseline, mravlje kiseline, octene kiseline, trifluorooctene kiseline, propionske kiseline, oksalne kiseline, malonske kiseline, sukcinske kiseline, fumarne kiseline, maleinske kiseline, mliječne kiseline, jabučne kiseline, vinske kiseline, limunske kiseline, etansulfonske kiseline, asparaginske i glutaminske kiseline.15. The method according to claim 14, where the acid is chosen from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid , malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ethanesulfonic acid, aspartic and glutamic acid.